Geographic Differences in Time to Culture Conversion in Liquid Media: Tuberculosis Trials Consortium Study 28. Culture Conversion Is Delayed in Africa

Tuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.In TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites.African TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found.Compared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved.ClinicalTrials.gov NCT00144417

Micro-RNA Regulation of Vascular Smooth Muscle Cells and Its Significance in Cardiovascular Diseases

Cardiovascular disease (CVD) is among the leading causes of death worldwide. Micro-RNAs (miRNAs), regulatory molecules that repress protein expression, have attracted considerable attention in CVD research. The vasculature plays a big role in CVD development and progression and dysregulation of vascular cells underlies the root of many vascular diseases. This review provides a brief introduction of the biogenesis of miRNAs and exosomes, followed by overview of the regulatory mechanisms of miRNAs in vascular smooth muscle cells (VSMCs) intracellular signaling during phenotypic switching, senescence, calcification and neointimal hyperplasia. Evidence of extracellular signaling of VSMCs and other cells via exosomal and circulating miRNAs was also presented. Lastly, current drawbacks and limitations of miRNA studies in CVD research and potential ways to overcome these disadvantages were discussed in detail. In-depth understanding of VSMC regulation via miRNAs will add substantial knowledge and advance research in diagnosis, disease progression and/or miRNA-derived therapeutic approaches in CVD research.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation

Influence of M. tuberculosis lineage variability within a clinical trial for pulmonary tuberculosis.

Recent studies suggest that M. tuberculosis lineage and host genetics interact to impact how active tuberculosis presents clinically. We determined the phylogenetic lineages of M. tuberculosis isolates from participants enrolled in the Tuberculosis Trials Consortium Study 28, conducted in Brazil, Canada, South Africa, Spain, Uganda and the United States, and secondarily explored the relationship between lineage, clinical presentation and response to treatment. Large sequence polymorphisms and single nucleotide polymorphisms were analyzed to determine lineage and sublineage of isolates. Of 306 isolates genotyped, 246 (80.4%) belonged to the Euro-American lineage, with sublineage 724 predominating at African sites (99/192, 51.5%), and the Euro-American strains other than 724 predominating at non-African sites (89/114, 78.1%). Uneven distribution of lineages across regions limited our ability to discern significant associations, nonetheless, in univariate analyses, Euro-American sublineage 724 was associated with more severe disease at baseline, and along with the East Asian lineage was associated with lower bacteriologic conversion after 8 weeks of treatment. Disease presentation and response to drug treatment varied by lineage, but these associations were no longer statistically significant after adjustment for other variables associated with week-8 culture status

Training in mitral valve surgery need not affect early outcomes and midterm survival: A multicentre analysis

Objective: Mitral valve surgery may be regarded as less favourable for training, due to greater mortality risk, technical complexity, and difficulty for the supervisor to observe. We examined this perception by reviewing a multicentre experience. Methods: We analysed a multicentre database over a 7-year period containing 2216 isolated and combined mitral procedures. Of these, 2048 were performed by consultants and 168 by trainees (92% vs 8%) of varying seniority. Preoperative characteristics, early postoperative outcomes and 6-year survival were compared between groups. Propensity-score matching was performed to correct for group differences. Results: Trainees were less likely to operate on patients, who had previously undergone coronary surgery (consultant 4.3% vs trainee 1.2%, p=0.043) and those with moderate to severe mitral regurgitation (86% vs 81%, p=0.012). There were no other statistically significant differences in preoperative variables, such as urgency, endocarditis and left-ventricular dysfunction. There were similar rates of mitral valve repair (48% vs 51%, p=0.48). Trainees were more likely to operate on rheumatic valve pathology (20% vs 28%, p=0.012). Intra-operatively, trainees had longer aortic cross-clamp times (119 ± 52 vs 136 ± 50. min, p=0.0001). At 30 days, mortality was comparable (4.5% vs 3.6%, p=0.56) with a trend towards higher any mortality/morbidity in consultant procedures (33% vs 26%, p=0.059). At 6 years, survival was similar (79 ± 1.4% vs 78 ± 4.0%, p=0.73). After derivation of 142 propensity-score-matched patient pairs, trainees cases still experienced longer cross-clamp times (121 ± 58 vs 137 ± 52. min, p=0.023), but there was similar 30-day mortality (4.2% vs 3.5%, p>0.99) and any mortality/morbidity (28% vs 24%, p=0.52). Six-year survival between matched pairs was also similar (74 ± 7.2% vs 80 ± 4.4%, p=0.64). Trainee status did not predict early or late adverse events after multivariate Cox regression with and without propensity-score adjustment. Conclusions: Trainee outcomes are not inferior even when corrected for risk. This suggests that excellent operative training and supervision can be achieved in mitral valve surgery. © 2011 European Association for Cardio-Thoracic Surgery

A propensity-score matched analysis on the impact of postoperative atrial fibrillation on the early and late outcomes after concomitant aortic valve replacement and coronary artery bypass graft surgery

Background: Postoperative atrial fibrillation (POAF) is a known complication of cardiac surgery. There is a paucity of data on the effects of POAF on short-term and long-term outcomes after concomitant aortic valve replacement and coronary artery bypass grafting (AVR-CABG ). Methods: We retrospectively reviewed data on patients without preexisting arrhythmia who underwent isolated first-time AVR-CABG between June 2001 and December 2009 using the Australasian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database Program. Preoperative characteristics, early postoperative outcomes and late survival were compared between patients who developed POAF and those who did not. Propensity score matching was performed to account for the differences between the two groups. Results: Isolated AVR-CABG surgery was performed in 2028 patients without preexisting arrhythmias at 18 Australian institutions, of whom 894 (44.1%) developed POAF. POAF patients were generally older (mean age, 75 vs. 73 years, P 24 h), multisystem failure and readmission within 30 days of surgery (all P < 0.05). Patients with POAF also had a significantly greater length of hospital stay (P < 0.001). Seven-year survival was not significantly different between the two groups (72 vs. 75%, P = 0.11). Conclusion: POAF was not associated with an increased risk of early or late mortality. It is, however, associated with poorer perioperative outcomes. It is important to evaluate potential treatment strategies for POAF